期刊
GLIA
卷 64, 期 6, 页码 952-962出版社
WILEY
DOI: 10.1002/glia.22974
关键词
Alzheimer's disease; protein metabolism; cholesterol
资金
- Takeda Science Foundation [25870906]
- Ritsumeikan Global Innovation Research Organization (R-GIRO), Ritsumeikan University
- Specific Research Fund of Hokuriku University, Japan
- Grants-in-Aid for Scientific Research [15K08050, 16K09767] Funding Source: KAKEN
One of the major neuropathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid beta-protein (Ab) in the brain. Ab accumulation seems to arise from an imbalance between Ab production and clearance. Neprilysin (NEP) and insulin-degrading enzyme (IDE) are the important Ab-degrading enzymes in the brain, and deficits in their expression may promote Ab deposition in patients with sporadic late-onset AD. Statins, which are used clinically for reducing cholesterol levels, can exert beneficial effects on AD. Therefore, we examined whether various statins are associated with Ab degradation by inducing NEP and IDE expression, and then evaluating the relation between activation of intracellular signaling transduction, inhibition of cholesterol production, and morphological changes to astrocytes. Treating cultured rat astrocytes with simvastatin and atorvastatin significantly decreased the expression of NEP but not IDE in a concentration- and time-dependent manner. The decrease in NEP expression was a result of activation of extracellular signal-regulated kinase (ERK) but not the reduction of cholesterol synthesis pathway. This NEP reduction was achieved by the release to the extracellular space of cultured astrocytes. Furthermore, the cultured medium prepared from simvastatin-and atorvastatin-treated astrocytes significantly induced the degradation of exogenous Ab. These results suggest that simvastatin and atorvastatin induce the increase of Ab degradation of NEP on the extracellular of astrocytes by inducing ERK-mediated pathway activity and that these reagents regulate the differential mechanisms between the secretion of NEP, the induction of cholesterol reduction, and the morphological changes in the cultured astrocytes.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据